Green and Catalytic Synthesis of Dominicalure I, Major Component of the Aggregation Pheromone of Rhyzopertha dominica (Fabricius) (Coleoptera: Bostrichidae)

Article abstract of DOI:10.1080/00397911.2014.997368

(Chemical Equation Presented). A new concise and efficient catalytic synthesis of dominicalure I, the male-produced aggregation pheromone of the grain borer Rhyzopertha dominica, is herein reported. The synthetic route was designed starting from easily available propanal through an organocatalytic key step and completed with biocatalytic procedures.

Full text of DOI:10.1080/00397911.2014.997368

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Green and Catalytic Synthesis of Dominicalure I,
Major Component of the Aggregation Pheromone
of Rhyzpertha dominica (Fabricius) (Coleoptera:
Bostrichidae
a
a
a
Estefanía Dibello , Gustavo Seoane & Daniela Gamenara
a
Organic Chemistry Department. Facultad de Química, Universidad de la República
UdelaR), Montevideo, Uruguay
(
Accepted author version posted online: 31 Dec 2014.
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To cite this article: Estefanía Dibello, Gustavo Seoane & Daniela Gamenara (2014): Green and Catalytic Synthesis
of Dominicalure I, Major Component of the Aggregation Pheromone of Rhyzpertha dominica (Fabricius) (Coleoptera:
Bostrichidae, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2014.997368
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Green and catalytic synthesis of Dominicalure I, major component of the
aggregation pheromone of Rhyzpertha dominica (Fabricius) (Coleoptera:
Bostrichidae
1
1
1
Estefanía Dibello , Gustavo Seoane , Daniela Gamenara
1
Organic Chemistry Department. Facultad de Química, Universidad de la República
UdelaR), Montevideo, Uruguay
(
Corresponding author Daniela Gamenara Organic Chemistry Department. Facultad de
Química, Universidad de la República (UdelaR). Gral. Flores 2124, 11800-Montevideo,
Uruguay E-mail: dgamenar@fq.edu.uy
Abstract
A new concise and efficient catalytic synthesis of Dominicalure I, the male-produced
aggregation pheromone of the grain borer Rhyzopertha dominica is here reported. The
synthetic route was designed starting from easily available propanal through an
organocatalytic key step, and completed with biocatalytic procedures.
KEYWORDS: Aggregation pheromones; Dominicalure I; Rhyzpoertha dominica;
organocatalysis, biocatalysis
1. INTRODUCTION
1

The lesser grain borer Rhyzopertha dominica (Fabricius) (Coleoptera: Bostrichidae) is a
worldwide distributed pest of stored grains. Together with Sitophilus spp., they constitute
the major stored grain pests, and R. dominica must be regarded as a primary pest due to
[
1]
its ability to disperse by flight, and high resistance to pesticides. Both, larvae and adults
cause significant damage in whole grains. The use of insect pheromones for pest
monitoring constitutes a valuable tool for the development of integrated pest management
[
2]
programs, with the aim of reducing the use of pesticides.
The male-produced aggregation pheromone of this beetle was isolated and identified as a
mixture of (S)-(+)-1-methylbutyl (E)-2-methyl-2-pentenoate and (S)-(+)-1-methylbutyl
[
3]
(
E)-2,4-dimethyl-2-pentenoate, Dominicalure I and II respectively (Figure 1), attracting
[
1]
both, males and females.
Both components of the pheromone were synthesized through different synthetic
approaches, but up to date, all of them involve either long synthetic sequences or
expensive reagents, making them inadequate for monitoring or control purposes. The first
synthesis of this pheromone was described by Williams et al. using (S)-2-pentanol,
[
3]
obtained from D-glutamic acid, as source of chirality. Almost a decade later, Liu and
Lin reported the synthesis of Dominicalure I and II with 30% overall yield and 90%
enantiomeric excess, employing a modification of Sharpless asymmetric epoxidation as
[
4]
the key step to introduce the adequate chirality. A stereoselective synthesis of
Dominicalure II was also described by using 1-silyl-1-stannylethenes as key
[
5]
intermediates. Razkin et al. reported the stereoselective synthesis of both components
2

of the pheromone, through an asymmetric reduction of 3-penten-2-one to the
corresponding (S)-3-penten-2-ol with (S)-BINAL-H as chiral auxiliary, and further
[
6]
diimide-mediated reduction of the double bond. Das and co-workers later reported an
efficient synthetic route exploiting the potential of Baylis-Hillman adducts for furnishing
[
7,8]
trisubstituted C=C bonds with (E)-configuration, as key intermediates.
Enzyme-
mediated introduction of the proper chirality in Dominicalure I and II was only described
by Morgan et al., with the Porcine Pancreatic Lipase (PPL)-mediated kinetic resolution of
[
9]
racemic (E)-3-penten-2-ol using trifluoromethyl laurate as acyl donor. After 45 hours,
the reaction achieved 39% conversion, and an enantiomeric ratio of 45. The unreacted
material was then subjected to a second resolution followed by further hydrogenation of
the remaining alcohol, yielding (S)-2-pentanol with high enantiomeric purity.
It is worth to notice, there are no recent reports regarding the preparation of either
components of the aggregation pheromone of R. dominica. This fact, gives this
contribution an additional impact, since it not only gives a concise, efficient and
environmentally responsible synthetic approach, but also is an up to date in the field of
pheromone chemistry.
Although pheromone chemistry has been widely developed during the last decades,
[
10]
stereoselective syntheses are still challenging tasks for classical organic chemistry. As
part of our ongoing program devoted to the synthesis of insect pheromones for
[
11-13]
developing monitoring programs for agricultural pests,
we attempt to introduce
catalytic methodologies (both bio- and organocatalytic ones) in our designed synthetic
3

routes, as a strategy to achieve efficient, economical and environmentally benign
procedures. The use of small organic molecules as catalysts for the preparation of chiral
[
14,15]
synthons was described for the first time by Eder and Hajos.
Nevertheless, it was not
until the decade of 2000, with the outstanding contribution of List, Lerner and Barbas
[
16]
III, that the high potential of this methodology was rediscovered and originated an
intense study of its synthetic possibilities.
Here we report a strategy that combines both, bio- and organocatalytic approaches for the
synthesis of Dominicalure I, component of the aggregation pheromone of R. dominica as
a single isomer. A similar procedure is currently being developed for the preparation of
Dominicalure II.
2
. RESULTS AND DISCUSSION
A retrosynthetic analysis of Dominicalure I shows that it can be obtained through an
esterification reaction of the corresponding ,β-unsaturated carboxylic acid with (S)-2-
pentanol or transesterification of its derivative. The carboxylic moiety can be prepared by
performing Pyrrolidine-catalyzed self-aldol condensation of propanal and further
oxidation, whereas (S)-2-pentanol comes from the enzyme-catalyzed kinetic resolution of
the corresponding racemic mixture (Scheme 1).
The first step in the synthetic sequence was the pyrrolidine-catalyzed self-aldol
condensation of propanal. The reaction was conducted in hexane at room temperature and
it was completed after 48 hours. After addition of a solution of 10% HCl the organic
4

solvent was distilled under atmospheric pressure, as well as the resulting ,β-unsaturated
[
17]
aldehyde 2 (Scheme 2). The reaction was highly stereoselective, giving trans-2 as a
single stereoisomer. It is worth to notice that herein we improved the efficiency of the
reaction also contributing to a greener synthetic approach, compared to previously
[18]
reported by Ishikawa and Saito, since we conducted it at room temperature, and with
less than 10% of the catalyst, obtaining aldehyde 2 with a better yield.
The next step is the oxidative esterification of 2. The oxidation of the unsaturated
aldehyde is not an easy task, given its instability. Looking for mild conditions, an easy
protocol developed by Corey was found, which, besides being adequate for the oxidation
[
19]
of labile ,β-unsaturated aldehydes, leads directly to an ester group. This method is
suitable to conjugated aldehydes, and effectively suppresses the isomerization of the
[
20]
double bond. The reaction involves the attack of a cyanide ion to the carbonyl group
generating a cyanohydrin. The subsequent oxidation of this intermediate to an acylnitrile
using MnO as oxidizing agent, and a final nucleophilic attack of methanol (also used as
2
solvent) to provide the corresponding methyl ester (Scheme 3). Secondary alcohols are
[
21]
not adequate nucleophiles for this reaction, so the ester of (S)-2-pentanol could not be
obtained directly.
[
17]
The corresponding methyl ester 3 was successfully obtained in 80% isolated yield. A
final treatment with (S)-2-pentanol is needed in order to obtain the pheromone
component.
5

Enantiomerically pure (S)-2-pentanol was obtained through the enzyme-catalyzed kinetic
resolution of racemic 2-pentanol using lipase B from Candida antarctica (CaL B,
Novozym 435) and vinyl butyrate as acylating agent. The reaction was performed in
absence of solvent, with orbital shaking (150 rpm) and at 37 ºC (Scheme 3). After 15
2
5
minutes, the reaction yielded the unreacted (S)-2-pentanol (49%, > 99% ee, [ ]D
=
+
13.5 (c = 0.5 g/100 ml, CHCl )) and the corresponding (R)-butylester (48%, 98% ee) –
3
[
22]
in agreement to Kaszlauskas’s rule–, which were successfully separated by column
chromatography. The same reaction was also carried out under microwave heating at 50
[
23]
°
C using a previously described protocol, and (S)-2-pentanol and the corresponding
(R)-butylester were obtained in 5 minutes with the same yields, and enantiomeric purities
(Scheme 4). The reactions were monitored by chiral gas chromatography. Both
[
24]
procedures also fit well with green chemistry principles, being more environmentally
[
25]
[26]
responsible than when using organic solvents or ionic liquids.
The last step in the synthetic route to Dominicalure I was the transesterification of 3 with
S)-2-pentanol. Although it is well known that (S)-secondary alcohols are not the
(
preferred substrates for lipases, the reaction was performed anyway due to the mildness
of this procedure. As expected, using CaL B as catalyst, the reaction rate was
[
4]
25
D
considerably slow, but Dominicalure I ([ ] = + 13.4 (c = 0.180 g/100 ml, ether) was
obtained with 90% yield and > 99% ee after 96 hours (Scheme 5). The same yield was
[23]
obtained under microwave irradiation and in solvent free conditions, but considerably
less time was needed, obtaining Dominicalure I in 4 hours.
6

In summary, the synthesis of Dominicalure I was achieved through a concise three steps
sequence, with an overall yield of 68% and > 99% ee starting from inexpensive materials.
3
. EXPERIMENTAL
3
.1. Materials And Methods
Solvents were purified and dried by conventional methods. Commercial reagents were
purchased from Sigma-Aldrich Inc. Lipase Novozym 435 (Lipase B from C. antarctica,
CaL B) was obtained from Novozymes. The purity of the reactants, as well as the
development of the reactions, were controlled using analytical TLC on silica gel
(Kieselgel HF 254 from Macherey-Nagel) and visualized with UV light (254 nm) and/or
p-anisaldehyde in acidic ethanolic solution. Flash chromatography was performed using
silica gel (Kieselgel 60, EM reagent, 230-400 mesh). Further analyses were performed by
gas chromatography (GC) in a Shimadzu 2010 equipment, with a FID detector. Chiral
gas chromatography was conducted using a Megadex DET-TBS (25 m 0.25 mm 0.25
m) column. Temperature program: 38 ºC (10 min) / 1 ºC/min / 60 ºC / 10 ºC/min / 200
ºC (5 min). TSPLIT: 150 ºC, T : 200 ºC. GC-MS analysis were performed using a
FID
Hewlett Packard 5890 GC-MS equipment coupled to a Hewlett Packard 5971 mass
spectrometer at an ionizing potential of 70 eV., with a DB5 column (Alltech, 30 m 0.25
mm 0.25 m) operated under constant carrier flow of 1 ml/min (He). Temperature
program: 70 ºC / 10 ºC/min / 320 ºC. TSPLIT: 220 ºC, interphase temperature: 250 ºC.
Injection (1 L) was in the split mode, and Total Ion Current detection was used. NMR
1
13
spectra ( H and C) were carried out in a Bruker Avance DPX 400 MHz equipment. All
experiments were performed at 30 ºC and CDCl was used as solvent. Proton chemical
3
7

shifts ( ) are reported in parts per million (ppm) downfield from TMS as an internal
reference, and carbon chemical shifts are reported in ppm relative to the center line of the
CDCl triplet (77.0 ppm). Optical rotations were measured at 25 ºC on a Zuzi 412
3
2
-1
polarimeter using a 0.5 dm cell. [ ] values are given in units of deg.cm .g and
D
concentration values are expressed in g/100ml. Biotransformations were conducted in an
orbital shaker Thermoforma model 420. All spectral data and optical rotations of known
intermediates and final products compares well with literature ones.
3
.2. Description Of The Experiments
E)-(S)-(+)-1-methylbutyl 2-methyl-2-pentenoate (Dominicalure I).
S)-2-Pentanol (0.2 g, 2.4 mmol) and lipase B from C. antarctica (Novozym 435, 30 mg)
[
4]
(
(
were added to a solution of 3 (200 mg, 1.6 mmol) in 3 ml of hexane. The reaction
mixture was stirred in an orbital shaker (150 rpm) at 37 ºC for 96 hours. The enzyme was
filtered and the crude mixture was purified by column chromatography (Hexane:AcOEt
2
5
1
9
5:5). Yield: 90%. [ ]D = +13.4 (Et O, c = 0.184 g/100 ml). H NMR: (ppm) = 6.72
2
(
tq; J = 7.3 Hz, J = 1.4 Hz, 1H), 4.95-5.02 (m; 1H), 2.18 (br q; J = 7.5 Hz, 2H), 1.82 (br
1 2
d; J = 1.3 Hz, 3H), 1.61-1.66 (m; 1H), 1.47-1.55 (m; 1H), 1.30-1.42 (m; 3H), 1.26 (d, J =
1
3
6
1
.3, 3H), 1.05 (t; J = 7.6 Hz, 3H), 0.92 (t; J = 7.3 Hz, 3H). C NMR: (ppm) = 168.0,
43.3, 127.6, 70.7, 38.2, 22.0, 20.0, 18.7, 14.0, 13.1, 12.2. GC: R = 11.67 min (DB5
t
+
column). MS (IE; 70 eV: m/z = 184 (M , 1%), 155 (5%), 141 (1%), 116 (5%), 115 (88%),
1
14 (10%), 99 (4%), 98 (8%), 97 (100%), 96 (3%), 87 (6%), 85 (2%), 71 (11%), 70
(
43%), 69 (50%), 68 (4%), 67 (9%), 55 (18%), 54 (4%), 53 (9%), 45 (8%), 43 (51%), 42
13%), 41 (63%), 40 (7%), 39 (18%), 32 (31%), 29 (14%).
(
8

SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
Finantial support for this work from ANII (Agencia Nacional de Investigación e
Innovación) and PEDECIBA (Programa de Desarrollo de las Ciencias Básicas) is
gratefully acknowledged. The authors also wish to thank Novozymes for the generous
gift of Novozym 435.
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06.
1
1

Scheme 1. Retrosynthetic analysis of Dominicalure I
1
2

Scheme 2. Pyrrolidine-catalyzed self-aldol condensation of propanal
1
3

Scheme 3. Oxidative esterification of 2 under Corey’s conditions
1
4

Scheme 4. CaL B-mediated kinetic resolution of 2-pentanol
1
5

Scheme 5. CaL B-catalyzed transesterification of 3 with (S)-2-pentanol, affording
Dominicalure I
1
6

Figure 1. Dominicalure I and II, components of the aggregation pheromone of
Rhyzopertha dominica (F.)
1
7